Project Abstract: This is an application for a renewal of a fiver-year Independent Scientist Award (K02) to assist in the continued protected time to allow Dr. Sandra Springer to continue her productive research career involving interventions that will improve integration of HIV and substance use disorder (SUD) treatment among persons living with HIV (PLH) and those at risk for HIV infection. This award will also increase her time to devote towards mentoring young investigators who share this interest. The prevalence of HIV infection is 28 to at least 50 times higher among people who inject drugs (PWID) compared to the general population. In North America, there were an estimated 267,000 persons living with HIV infection (PLHs) among 2 million PWIDs in 2012. Opioids represent the dominant class of injected agent, and in 2013 517,000 adults reported heroin use within the past year, representing an approximately 150% increase compared to 2007. Medication-assisted treatment (MAT) for opiate addiction, combined with needle and syringe exchange programs (NESP) have substantially reduced the risk of HIV transmission in PWIDs. Moreover, MAT reduces mortality among HIV-positive PWIDs (which is otherwise 3-fold higher than in PWIDs who are HIV-negative). MAT is predominantly available in the form of opioid agonist treatment with methadone or buprenorphine, with emerging use of opioid antagonist treatments (e.g. extended-release naltrexone). However, there are no recommendations currently available to guide the selection of MAT agent. Moreover, despite substantial evidence for immunomodulatory effects of opioids on immune responses, no studies have employed systems biology methods to evaluate MAT agents for their effects on parameters such as chronic inflammation?particularly important for HIV disease progression and present even in elite controllers or individuals who have achieved virologic control without antiretroviral therapy (ART). To address these questions, Dr. Springer has been awarded a NIDA funded 5 year R01 to evaluate innate immunity and inflammation with her co-PI at Yale School of Medicine, Dr. Shaw, to carry out a prospective, longitudinal study of HIV-positive (on ART) vs. HIV-negative PWIDs starting MAT, recruited from the largest drug treatment center in New Haven, Connecticut. The strength of this proposal is that Dr. Springer is: (1) experienced in HIV and Addiction Medicine; (2) experienced in the novel use of pharmacologic interventions (MAT) to treat SUDs to prevent relapse to opioid and alcohol use as a means to improve HIV viral suppression; (3) has over 15 years experience of conducting NIH-funded research among PLH with SUD and using MAT interventions; and (4) is a co-PI on a successful R01 affiliated with this application that is extending her experience with using systems biology to evaluate MAT on chronic inflammation of HIV infection. As such, the individual, our health care system and society have a high likelihood to benefit ? especially on the reduction of HIV within the community.